Abstract: nature communications Article https://doi.org/10.1038/s41467-022-32045-1 SARS-CoV-2 VOC type and biological sex affect molnupiravir efficacy in severe COVID-19 dwarf hamster model Received: 1 March 2022 Check for updates 1234567890():,; 1234567890():,; Accepted: 14 July 2022 Carolin M. Lieber1,5, Robert M. Cox 1,5, Julien Sourimant 1, Josef D. Wolf 1, Kate Juergens2, Quynh Phung2, Manohar T. Saindane3, Meghan K. Smith 3, Zachary M. Sticher 3, Alexander A. Kalykhalov3, Michael G. Natchus3, George R. Painter3, Kaori Sakamoto4, Alexander L. Greninger2 & Richard K. Plemper 1 SARS-CoV-2 variants of concern (VOC) have triggered infection waves. Oral antivirals such as molnupiravir promise to improve disease management, but efficacy against VOC delta was questioned and potency against omicron is unknown. This study evaluates molnupiravir against VOC in human airway epithelium organoids, ferrets, and a lethal Roborovski dwarf hamster model of severe COVID-19-like lung injury. VOC were equally inhibited by molnupiravir in cells and organoids. Treatment reduced shedding in ferrets and prevented transmission. Pathogenicity in dwarf hamsters was VOC-dependent and highest for delta, gamma, and omicron. All molnupiravir-treated dwarf hamsters survived, showing reduction in lung virus load from one (delta) to four (gamma) orders of magnitude. Treatment effect size varied in individual dwarf hamsters infected with omicron and was significant in males, but not females. The dwarf hamster model recapitulates mixed efficacy of molnupiravir in human trials and alerts that benefit must be reassessed in vivo as VOC evolve. By May 2022, SARS-CoV-2 has resulted in over 522 million cases and >6.2 million deaths worldwide1. Vaccines are widely available2,3, but recuring global infection waves have been fueled by limited longevity of vaccine-induced immunity, the hesitancy of population subgroups to vaccinate4,5, and increasingly contagious and/or vaccine-insensitive variants of concern (VOC) alpha (B.1.1.7 lineage), beta (B.1.351 lineage), gamma (P.1 lineage), delta (B.1.617.2 lineage), and omicron (B1.1.529 lineage)6,7. VOC delta was the prevalent circulating variant during Summer and Fall 2021 due to replication to high titers, prolonged shedding from infected individuals, and propensity to induce breakthrough infections in vaccinees8–10. Since its first appearance in November 2021, VOC omicron has rapidly replaced delta as the dominant circulating strain in most geographical regions11, propelled by sharply reduced sensitivity to neutralizing antibodies directed against earlier lineages and greatly increased infectivity12. Although clinical signs associated with VOC omicron are typically milder than those of its predecessors, record-high daily infection rates have driven high absolute hospitalization numbers, creating an urgent need for therapeutics to improve disease management. Molnupiravir was the first orally available SARS-CoV-2 inhibitor approved for outpatient use against COVID-1913. Intermediate results of the early months of a large efficacy trial revealed an encouraging 50% reduction in hospitalizations in the treatment group, but later analysis of the full dataset showed only a 30% lower hospitalization rate overall14. Based on the geographical location of trial participants and VOC prevalence in the earlier versus later phase of the trial, an 1 Center for Translational Antiviral Research, Institute for Biomedical Sciences, Georgia State..